Glucocorticoid

Dexamethasone binds more powerfully to the glucocorticoid receptor than cortisol does. Dexamethasone is based on the cortisol structure but differs in three positions (extra double bond in the A-ring between carbons 1 and 2 and addition of a 9-α-fluoro group and a 16-α-methyl substituent).

Glucocorticoids (GCs) are a class of steroid hormones that bind to the glucocorticoid receptor (GR),[1] which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from its role in the regulation of the metabolism of glucose, its synthesis in the adrenal cortex, and its steroidal structure (see structure to the right). A less common synonym is glucocorticosteroid.

GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over the counter.[2] They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. This includes mainly inhibitory effects on lymphocyte proliferation (treatment of lymphomas and leukemias) and mitigation of side effects of anticancer drugs.

Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. In technical terms, "corticosteroid" refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for "glucocorticoid." Glucocorticoids are chiefly produced in the zona fasciculata of the adrenal cortex, whereas mineralocorticoids are synthesized in the zona glomerulosa.

Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.

Steroidogenesis showing glucocorticoids in green ellipse at right - it is not a strictly bounded group, but a continuum of structures with increasing glucocorticoid effect, with the primary example being cortisol.

As discussed in more detail below, glucocorticoids function through interaction with the glucocorticoid receptor:

up-regulate the expression of anti-inflammatory proteins.

down-regulate the expression of proinflammatory proteins.

Glucocorticoids are also shown to play a role in the development and homeostasis of T lymphocytes. This has been shown in transgenic mice with either increased or decreased sensitivity of T cell lineage to glucocorticoids.[3]

The name "glucocorticoid" derives from early observations that these hormones were involved in glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood.

Metabolic effects:

Stimulation of gluconeogenesis, in particular, in the liver: This pathway results in the synthesis of glucose from nonhexose substrates, such as amino acids and glycerol from triglyceride breakdown, and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids.

Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose

Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.

Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to osteoporosis), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids.[3]

Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extrauterine lung function. Mice with homozygous disruptions in the corticotropin-releasing hormone gene (see below) die at birth due to pulmonary immaturity. In addition, glucocorticoids are necessary for normal brain development, by initiating terminal maturation, remodeling axons and dendrites, and affecting cell survival[4] and may also play a role in hippocampal development.

Glucocorticoids act on the hippocampus, amygdala, and frontal lobes. Along with adrenaline, these enhance the formation of flashbulb memories of events associated with strong emotions, both positive and negative.[5] This has been confirmed in studies, whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect was more important in men). The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation. In multiple animal studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction of the neurons in this area of the brain, which has been connected to memory performance.[6][7][8]

Glucocorticoids have also been shown to have a significant impact on vigilance (attention deficit disorder) and cognition (memory). This appears to follow the Yerkes-Dodson curve, as studies have shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern, much like the Yerkes-Dodson curve. For example, long-term potentiation (LTP; the process of forming long-term memories) is optimal when glucocorticoid levels are mildly elevated, whereas significant decreases of LTP are observed after adrenalectomy (low-GC state) or after exogenous glucocorticoid administration (high-GC state). Elevated levels of glucocorticoids enhance memory for emotionally arousing events, but lead more often than not to poor memory for material unrelated to the source of stress/emotional arousal.[9] In contrast to the dose-dependent enhancing effects of glucocorticoids on memory consolidation, these stress hormones have been shown to inhibit the retrieval of already stored information.[10] Long-term exposure to glucocorticoid medications, such as asthma and anti-inflammatory medication, has been shown to create deficits in memory and attention both during and, to a lesser extent, after treatment,[11][12] a condition known as "steroid dementia."[13]

Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume by regulating body’s action to atrial natriuretic peptide (ANP). Centrally, glucocorticoids could inhibit dehydration induced water intake;[14] peripherally, glucocorticoids could induce a potent diuresis.[15]

The opposite mechanism is called transcriptional repression, or transrepression. The classical understanding of this mechanism is that activated GR binds to DNA in the same site where another transcription factor would bind, which prevents the transcription of genes that are transcribed via the activity of that factor.[17][18] While this does occur, the results are not consistent for all cell types and conditions; there is no generally accepted, general mechanism for transrepression.[18]

New mechanisms are being discovered where transcription is repressed, but the activated GR is not interacting with DNA, but rather with another transcription factor directly, thus interfering with it, or with other proteins that interfere with the function of other transcription factors. This latter mechanism appears to be the most likely way that activated GR interferes with NF-κB - namely by recruiting histone deacetylase, which deacetylate the DNA in the promoter region leading to closing of the chromatin structure where NF-κB needs to bind.[17][18]

Activated GR has effects that have been experimentally shown to be independent of any effects on transcription and can only be due to direct binding of activated GR with other proteins or with mRNA.[17][18]

For example Src kinase which binds to inactive GR, is released when a glucocorticoid binds to GR, and phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in inflammation, epidermal growth factor (EGF), reducing its activity, which in turn results in reduced creation of arachidonic acid - a key proinflammatory molecule. This is one mechanism by which glucocorticoids have an anti-inflammatory effect.[17]

A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in both pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) and pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water; renal physiology). Because they permeate the intestines easily, they are administered primarily per os (by mouth), but also by other methods, such as topically on skin. More than 90% of them bind different plasma proteins, though with a different binding specificity. Endogenous glucocorticoids and some synthetic corticoids have high affinity to the protein transcortin (also called corticosteroid-binding globulin), whereas all of them bind albumin. In the liver, they quickly metabolize by conjugation with a sulfate or glucuronic acid, and are secreted in the urine.

Glucocorticoid potency, duration of effect, and the overlapping mineralocorticoid potency vary. Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol.

The data below refer to oral dosing, except where mentioned. Oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Fludrocortisone, DOCA (Deoxycorticosterone acetate), and aldosterone are, by definition, not considered glucocorticoids, although they may have minor glucocorticoid potency, and are included in this table to provide perspective on mineralocorticoid potency.

Glucocorticoids may be used in low doses in adrenal insufficiency. In much higher doses, oral or inhaled glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment for asthma. They are also administered as post-transplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes. Newly emerging evidence showed that glucocorticoids could be used in the treatment of heart failure to increase the renal responsiveness to diuretics and natriuretic peptides.

Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing. This is approximately 6–12 mg/m²/day of hydrocortisone (m² refers to body surface area (BSA), and is a measure of body size; an average man's BSA is 1.9 m²).

The major mechanism for this immunosuppression through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB). NF-κB is a critical transcription factor involved in the synthesis of many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote the immune response. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to mount a response.[2]

Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect - glucocorticoid-induced apoptosis. The effect is more prominent in immature T cells still inside in the thymus, but peripheral T cells are also affected. The exact mechanism underlying this glucocorticoid sensitivity still remains to be elucidated.[citation needed]

Resistance to the therapeutic uses of glucocorticoids can present difficulty; for instance, 25% of cases of severe asthma may be unresponsive to steroids. This may be the result of genetic predisposition, ongoing exposure to the cause of the inflammation (such as allergens), immunological phenomena that bypass glucocorticoids, and pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism).[21]

Glucocorticoids could be used in the treatment of decompensated heart failure to potentiate renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large dose of loop diuretics.[24][25][26][27][28][29][30]

Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on the elaboration of selectively acting glucocorticoid drugs. Side effects include:

In addition to the effects listed above, use of high-dose steroids for more than a week begins to produce suppression of the patient's adrenal glands because the exogenous glucocorticoids suppress hypothalamic corticotropin-releasing hormone and pituitary adrenocorticotropic hormone. With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid.

During this recovery time, the patient is vulnerable to adrenal insufficiency during times of stress, such as illness. While suppressive dose and time for adrenal recovery vary widely, clinical guidelines have been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient. The following is one example:

If patients have been receiving daily high doses for five days or less, they can be abruptly stopped (or reduced to physiologic replacement if patients are adrenal-deficient). Full adrenal recovery can be assumed to occur by a week afterward.

If high doses were used for six to 10 days, reduce to replacement dose immediately and taper over four more days. Adrenal recovery can be assumed to occur within two to four weeks of completion of steroids.

If high doses were used for 11–30 days, cut immediately to twice replacement, and then by 25% every four days. Stop entirely when dose is less than half of replacement. Full adrenal recovery should occur within one to three months of completion of withdrawal.

If high doses were used more than 30 days, cut dose immediately to twice replacement, and reduce by 25% each week until replacement is reached. Then change to oral hydrocortisone or cortisone as a single morning dose, and gradually decrease by 2.5 mg each week. When the morning dose is less than replacement, the return of normal basal adrenal function may be documented by checking 0800 cortisol levels prior to the morning dose; stop drugs when 0800 cortisol is 10 μg/dl. Predicting the time to full adrenal recovery after prolonged suppressive exogenous steroids is difficult; some people may take nearly a year.

Flare-up of the underlying condition for which steroids are given may require a more gradual taper than outlined above.